Synthesis of Enantiomerically Pure 3-Substituted Piperazine-2-acetic Acid Esters as Intermediates for Library Production

Abstract

The piperazine heterocycle is broadly exploited in FDA-approved drugs and biologically active compounds, but its chemical diversity is usually limited to ring nitrogen substitutions, leaving the four carbon atoms underutilized. Using an efficient six-step synthesis, chiral amino acids were transformed into 3-substituted piperazine-2-acetic acid esters as diastereomeric mixtures whose cis and trans products (dr 0.56 → 2.2:1, respectively) could be chromatographically separated. From five amino acids (both antipodes) was obtained a complete matrix of 20 monoprotected chiral 2,3-disubstituted piperazines, each as a single absolute stereoisomer, all but one in multigram quantities. In keeping with our overall purpose of constructing more Csp-enriched compound libraries for drug discovery, these diverse and versatile piperazines can be functionalized on either nitrogen atom, allowing them to be used as scaffolds for parallel library synthesis and as intermediates for the production of novel piperazine compounds.

Stereodivergent access to all four stereoisomers of chiral tetrahydrobenzo[f][1,4]oxazepines, through highly diastereoselective multicomponent Ugi–Joullié reaction

“…The key step for the synthesis of cyclic imines 3 is the Mitsunobu coupling of salicylaldehydes 1 with Boc-protected aminoalcohols 7. All employed alcohols 7 are known, [43][44][45] and they can be easily synthesized by reduction of Boc-protected a-amino acids, in turn commercially available in both enantiomeric forms with a wide variety of R 2 substituents. Alternatively, some of them (7d, 7e) have been obtained by protection of the commercially available enantiopure amino alcohols (see ESI †).…”

Recent progress toward the asymmetric synthesis of carbon-substituted piperazine pharmacophores and oxidative related heterocycles

“…To complete the series, for the synthesis of homochiral 3-substituted-piperazine-2-acetic acid esters as intermediates for library production, the group of Santini and Young at Baylor College of Medicine adopted an “inter” retrosynthetic strategy entailing the formation of a second stereocenter by an intermolecular aza-Michael reaction of ethanolamine to an acrylate also derived from a homochiral amino acid 88 ( Scheme 16 ). 52 …”

“…The separation of some piperazines proved to be difficult at this point, but Boc reprotection of the nitrogen at the 4-position rendered the remaining diastereomers 109 cis and 110 trans separable by normal-phase column chromatography. 52 In the trans products, substituents at C 2 and C 3 are diaxial to minimize the allylic 1,3-strain with the nosyl amide as well as to avoid steric clashes that would occur between adjacent diequatorial groups. 27 The strategic preparation and separation of diastereomeric mixtures proved to be key to the efficient implementation of this systematic chemical diversity (SCD) strategy.…”

“… 27 The strategic preparation and separation of diastereomeric mixtures proved to be key to the efficient implementation of this systematic chemical diversity (SCD) strategy. 51 , 52 …”

Chemical composition of DNA-encoded libraries, past present and future

“…In another example, the DEC-TEC Core at Baylor College of Medicine synthesized a set of enantiomerically pure substituted, piperazine acetic acid esters that are well-poised for subsequent diversification 38,39 . These units could be easily installed into traditional DNAencoded libraries and be transformed using already-established chemistries to afford skeletally diverse, high diversity libraries.…”